Substituted thiazoles and the use thereof as inhibitors of plasminogen activator inhibitor-1

ABSTRACT

The present invention relates to the use of aminothiazole derivatives of Formula I of as inhibitors of PAI-1, and to novel classes of aminothiazole derivatives, their synthesis and their use as inhibitors of PAI-1. It has been discovered that compounds of Formula I:  
                 
 
     or a solvate, hydrate or a pharmaceutically acceptable salt thereof, wherein  
     Y, Ar 1 , Ar 2 , R 1 , R 2 , Z, m and n are described in the specification, inhibit plasminogen activator inhibitor-1 (PAI-1). These compounds can be used in the prophylaxis or for the treatment of thrombosis, angina pectoris, cerebral infarction, myocardial infarction, pulmonary infarction, intra-atrial thrombus in atrial fibrillation, deep venous thrombus, disseminated intravascular coagulation syndrome, diabetic complications, restenosis and stroke.

BACKGROUND OF THE INVENTION

[0001] This application claims the priority benefit under 35 U.S.C. §119 of U.S. Provisional App. No. 60/194,505, filed Apr. 3, 2000, theentirety of which is incorporated by reference herein.

1. Field of the Invention

[0002] The present invention is in the field of inhibitors ofplasminogen activator inhibitor-1 (PAI-1) activity. More particularly,the invention relates to the use of substituted thiazoles as inhibitorsof PAI-1, and to novel classes of 2-substituted thiazole derivatives,their synthesis and their use as inhibitors of PAI-1.

2. Related Art

[0003] PAI-1 is a naturally occurring serine protease inhibitor, orserpin, that rapidly inhibits the activity of several proteases,including tissue plasminogen activator (tPA) and urokinase plasminogenactivator (uPA), by forming equimolar, irreversible complexes that areinternalized and degraded. In this capacity, PAI-1 plays a major role inpreventing fibrinolysis by decreasing the level of tPA and/or uPA, andconsequently, the level of plasminogen converted to plasmin. Plasmin isan enzyme critical to the lysis of fibrin clots and works by cleavingfibrin to small soluble products.

[0004] PAI-1 can contribute to a variety of coronary diseases byretarding the clearance of thrombi. Elevated levels of PAI-1 have beendescribed to correlate with an increased risk of atherosclerosis (Lupu,F., et al., Arteriosclerosis and Thrombosis 13:1090-1100 (1993)), deepvein thrombosis (Patrassi, G. M., et al., Fibrinolysis 6:99-102 (1992))and of thrombosis during sepsis, surgery and trauma (Kluft, C., et al.,Scand. J. Clin. Lab. Invest. 45:605-610 (1985)). Elevated PAI-1 levelsare also thought to contribute to the high incidence of coronary diseasein individuals with Type 2 diabetes (Sobel, B. E., et al., Circulation97(22):2213-2221 (1998)), obese individuals (Lundgren, C. H., et al.,Circulation 93(1):106-110 (1996)), and the elderly (Lupu, F., et al.,Arteriosclerosis and Thrombosis 13:1090-1100 (1993)).

[0005] Increased PAI-1 has been demonstrated in human atheroscleroticvessel walls and may contribute to the impaired plasma fibrinolyticcapacity in patients at high risk of atherothrombotic events. Theatherosclerotic process begins with an injury to the inner lining of theblood vessel, the endothelium. Smooth muscle cells migrate from theirnormal location in the media to the intima, where they divide and makeup a bulk lesion.

[0006] Immunohistochemical analyses have revealed that most of the PAI-1in the thickened intima of early lesions is located in and aroundneointimal smooth muscle cells and possibly macrophages. Both of thesecell types can become lipid-laden foam cells that form fatty streaks,another hallmark feature of atherosclerosis.

[0007] In advanced lesions, larger amounts of PAI-1 are expressed bysmooth muscle cells and macrophages in the necrotic core. Most of thePAI-1 of this advanced stage is in complex tPA, suggesting that PAI-1has an important function in modulating mural tPA activity (Padro, T.,et al., Arterioscler. Thromb. Vasc. Biol. 15:893-902 (1995) and Saweh,H., et al., Circ. Res. 73:671-680 (1993)). These findings have beensupported with experimental work in rabbits that demonstrated anincrease in PAI-1 expression in activated endothelial cells, macrophagesand smooth muscle cells in response to sustained mechanical injury. Theincrease in PAI-1 transcription paralleled the severity of vascularlesions induced and was increased in hypercholesterolemic rabbits(Kruithof, E. K. O., et al., Blood 70:1645-1653 (1987)). These resultssuggest that enhanced PAI-1 expression is a feature of earlyatherosclerosis and that a PAI-1 inhibitor may be effective preventivetherapeutics for high risk patients.

[0008] A PAI-1 inhibitor may also serve as an anticancer agent. Anantibody to PAI-1 has been shown to suppress metastasis in severalcancer models (Tsuchiya, H., et al., Gen. Diag., Pathol. 141:41-48(1995)). In cultured lung cancer cells, PAI-1 is necessary for optimuminvasion (Liu, G., et al., Int. J. Cancer 60:501-506 (1995)). Further,cancer invasion and tumor vascularization have been prevented in PAI-1knockout mice implanted with malignant murine keratinocytes (Bajou, K.,et al., Nature Med. 4(8):923-928 (1998)). This indicates that PAI-1plays an integral role in tumor progression.

[0009] PAI-1 is also expressed at high levels by smooth muscle andendothelial cells, and it regulates the proteolytic activity surroundingthe formation of blood vessels. A PAI-1 inhibitor may be suitable as ananti-angiogenic agent by hindering proper vessel formation around tumor.In fact, transduced endothelial cells that express decreased PAI-1activity compared with normal endothelial cells were found to form largeectactic sac-like structures resembling haemangiomas when cultured infibrin gels, suggesting abnormal vessel formation (Lawrence, D. A., etal., J. Biol. Chem. 269(21):15223-15229 (1994)).

[0010] U.S. Pat. No. 4,942,242 discloses compounds of the followingFormula:

[0011] wherein n is 3 or 4. These compounds are disclosed to be usefulas inhibitors of blood platelet aggregation.

[0012] JP 61016274 describes, for example, the following thiazolederivatives that are stated to have platelet aggregation inhibitoryactivity:

[0013] wherein R¹ is CH₂COOH or CHMeCOOH and R², R³ and R⁴ areindependently selected from the group consisting of H, CH₃, OCH₃ and Cl,and

[0014] A need exists in the art for compounds that are potent and/orselective inhibitors of PAI-1.

SUMMARY OF THE INVENTION

[0015] It has now been discovered that thiazole derivatives of FormulaI:

[0016] or a solvate, hydrate or a pharmaceutically acceptable saltthereof, wherein

[0017] Y is —N—, —C(R³)— or —CH(R³)—, wherein

[0018] R³ is selected from the group consisting of hydrogen, cyano,C(CN)₃, N(CN)₂, trifluoromethyl, halogen, alkyl, cycloalkyl, aryl andheteroaryl radical, all of which can be optionally substituted;

[0019] Ar¹ and Ar², which can be the same or different, are anoptionally substituted aryl or an optionally substituted heteroarylradical;

[0020] m is 0 or 1, provided that when Y is —N— or —C(R³)—, then m is 1,and when Y is —CH(R³)—, then m is 0;

[0021] R¹ is selected from the group consisting of hydrogen, alkyl,cycloalkyl, and aryl or heteroaryl radical, all of which can beoptionally substituted; and

[0022] R² is hydrogen, or an optionally substituted aryl or anoptionally substituted heteroaryl radical; with the provisos that

[0023] when Y is N, R¹ and R² are hydrogen and Ar² is an optionallysubstituted phenyl, then Ar¹ is other than a phenyl group substitutedwith carboxyalkyl or an alkyl ester of carboxyalkyloxy;

[0024] when Y is N, R¹ is hydrogen, and Ar² and R² are both a phenylgroup, then Ar¹ is other than a phenyl group substituted withcarboxyalkyl; or

[0025] when Y is N, R¹ and R² are hydrogen and Ar² is naphthyl, then Ar¹is other than a phenyl group substituted with carboxyalkyl,

[0026] inhibit plasminogen activator inhibitor-1 (PAI-1). Thesecompounds can be used in the prophylaxis or for the treatment ofthrombosis, angina pectoris, cerebral infarction, myocardial infarction,pulmonary infarction, intra-atrial thrombus in atrial fibrillation, deepvenous thrombus, disseminated intravascular coagulation syndrome,diabetic complications, restenosis and stroke.

[0027] Accordingly, the present invention provides a method ofinhibiting plasminogen activator inhibitor-1. The method comprisesadministering to a mammal in need thereof an effective amount of acompound of Formula I.

[0028] Also, the present invention provides a method for preventing ortreating one or more of thrombosis, angina pectoris, cerebralinfarction, myocardial infarction, pulmonary infarction, intra-atrialthrombus in atrial fibrillation, deep venous thrombus, disseminatedintravascular coagulation syndrome, diabetic complications, restenosis,for example, after percutaneous transluminal coronary angioplasty, orstroke by administering to a mammal in need thereof an effective amountof a compound of Formula I.

[0029] A number of compounds useful in the present invention have notbeen heretofor reported. Thus, the present invention also provides novelthiazole derivatives included in Formula I. Also, the present inventionprovides a method for preparing the novel compounds included in FormulaI.

[0030] Further, the present invention provides pharmaceutical andveterinary compositions for inhibiting plasminogen activatorinhibitor-1, comprising an effective amount of one or more of thecompounds of Formula I-VI in a mixture with one or more pharmaceuticallyacceptable carriers or diluents.

[0031] Additional embodiments and advantages of the invention will beset forth in part in the description as follows, and in part will beobvious from the description, or may be learned by practice of theinvention. The embodiments and advantages of the invention will berealized and attained by means of the elements and combinationsparticularly pointed out in the appended claims.

[0032] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Applicants have discovered that plasminogen activator inhibitor-1can be effectively inhibited by compounds of Formula I:

[0034] or a solvate, hydrate or a pharmaceutically acceptable saltthereof, wherein

[0035] Y is —N—, —C(R³)— or —CH(R³)—, wherein

[0036] R³ is selected from the group consisting of hydrogen, cyano,C(CN)₃, N(CN)₂, trifluoromethyl, halogen, alkyl, cycloalkyl, aryl andheteroaryl radical, all of which can be optionally substituted;

[0037] Ar¹ and Ar², which can be the same or different, are anoptionally substituted aryl or an optionally substituted heteroaryl;

[0038] m is 0 or 1, provided that when Y is —N— or —C(R³)—, then m is 1,and when Y is —CH(R³)—, then m is 0;

[0039] R¹ is selected from the group consisting of hydrogen, alkyl,cycloalkyl, and aryl or heteroaryl radical, all of which can beoptionally substituted; and

[0040] R² is hydrogen, or an optionally substituted aryl or anoptionally substituted heteroaryl radical;

[0041] with the provisos that

[0042] when Y is N, R¹ and R² are hydrogen and Ar² is an optionallysubstituted phenyl, then Ar¹ is other than a phenyl group substitutedwith carboxyalkyl or an alkyl ester of carboxyalkyloxy;

[0043] when Y is N, R¹ is hydrogen, and Ar² and R² are both a phenylgroup, then Ar¹ is other than a phenyl group substituted withcarboxyalkyl; or

[0044] when Y is N, R¹ and R² are hydrogen and Ar² is naphthyl, then Ar¹is other than a phenyl group substituted with carboxyalkyl.

[0045] Therefore, these compounds can be used in the prophylaxis or forthe treatment of thrombosis, angina pectoris, cerebral infarction,myocardial infarction, pulmonary infarction, intra-atrial thrombus inatrial fibrillation, deep venous thrombus, disseminated intravascularcoagulation syndrome, diabetic complications, restenosis, for example,after percutaneous transluminal coronary angioplasty, and stroke.

[0046] Preferred compounds falling within the scope of Formula I includecompounds wherein Ar¹ and Ar² are independently selected from the groupconsisting of phenyl, biphenyl, naphthyl, tetrahydronaphthyl, thienyl,benzothienyl, furyl, benzofuryl, thiazolyl, imidazolyl, isoxazolyl,pyrrolyl and pyrazolyl, any of which can be optionally substituted. Morepreferably, Ar¹ is selected from the group consisting of phenyl,naphthyl, tetrahydronaphthyl, biphenyl and isoxazolyl and Ar² is phenyl.Especially, Ar¹ is selected from the group consisting oftetrahydronaphthyl, biphenyl and isoxazolyl.

[0047] The aryl and heteroaryl groups are preferably optionallysubstituted by one or more substituents independently selected from thegroup consisting of alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl,amino, aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol,acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl,—NHR⁴, —NR⁴R⁵, phenoxy, and benzyloxy, wherein R⁴ and R⁵ are selectedfrom the group consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl,—O—C(O)-alkyl and —C(O)NH-aryl. More preferably, the optionalsubstituents are selected from the group consisting of C₁₋₆ alkyl,fluoro, chloro, bromo, trifluoro(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, nitro, cyano,carboxy, —C(O)(C₁₋₆)alkyl, benzyloxy, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, —C(O)O(C₁₋₆)alkyl, —O—C(O)(C₁₋₆)alkyl and—C(O)NH(C₁₋₆)alkyl.

[0048] Preferably, R¹ is selected from the group consisting of H, C₁₋₆alkyl, C₃₋₇ cycloalkyl and phenyl substituted with trifluoro(C₁₋₆)alkyl,nitro, hydroxy, C₁₋₄ alkyl, halogen, amino, —NHR⁴, wherein R⁴ isselected from the group consisting of C₁₋₆ alkyl, —C(O)(C₁₋₆)alkyl,aroyl, —C(O)NH(C₁₋₃)alkyl and —C(O)NH-aryl.

[0049] Preferably, R² is selected from the group consisting of hydrogenand a phenyl radical optionally substituted by trifluoro(C₁₋₆)alkyl,nitro, hydroxy, C₁₋₆ alkoxy, halogen, amino, cyano, C₁₋₆ alkyl and—NHR⁴, wherein R⁴ is selected from the group consisting of C₁₋₆ alkyl,—C(O)(C₁₋₆)alkyl, aroyl, —C(O)NH—(C₁₋₃) alkyl and —C(O)NH-aryl.

[0050] Preferably, R¹ and R² are both hydrogen in Formula I.

[0051] One group of useful compounds of the invention are compounds ofFormula II:

[0052] or a solvate, hydrate or a pharmaceutically acceptable saltthereof, wherein

[0053] Ar²¹ is an optionally substituted aryl or an optionallysubstituted heteroaryl radical;

[0054] Ar²² is a substituted aryl or an optionally substitutedheteroaryl radical;

[0055] R²¹ is selected from the group consisting of hydrogen, alkyl,cycloalkyl, and aryl or heteroaryl radical, all of which can beoptionally substituted;

[0056] R²² is hydrogen or an optionally substituted aryl or anoptionally substituted heteroaryl radical, with the provisos that

[0057] when R²¹ and R²² are hydrogen and Ar²² is substituted phenyl,then Ar²¹ is other than a phenyl group substituted with carboxyalkyl;

[0058] when R²¹ is hydrogen, and Ar²² and R²² are both a phenyl group,then Ar²¹ is other than a phenyl group substituted with carboxyalkyl; or

[0059] when R²¹ and R²² are hydrogen and Ar²² is naphthyl, then Ar²¹ isother than a phenyl group substituted with carboxyalkyl.

[0060] Preferably, the aryl radical is selected from the groupconsisting of phenyl, biphenyl, naphthyl and tetrahydronapthyl. Theheteroaryl radical is preferably isoxazolyl.

[0061] Preferably, Ar²² is a phenyl group substituted with one or moreof alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl,alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino,acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR⁴,—NR⁴R⁵, phenoxy, and benzyloxy, wherein R⁴ is selected from the groupconsisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and—C(O)NH-aryl. More preferably, Ar²² is a phenyl group substituted withone or more of C₁₋₆ alkyl, fluoro, chloro, bromo, trifluoro(C₁₋₆)alkyl,hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy,nitro, cyano, carboxy, —C(O)O—(C₁₋₆)alkyl and benzyloxy.

[0062] One group of preferred compounds of Formula II are those whereinAr²¹ is a phenyl group substituted with 3,4-difluoro, 2,4-difluoro,bromo, trifluoromethyl, 3,4-dichloro, and 2,4-dichloro.

[0063] One group of preferred compounds of Formula II are those whereinAr²² is a phenyl group substituted with carboxy, cyano, nitro,trifluoromethyl, 3,5-dichloro, 3,4-dichloro, 2,4-dichloro,2,4,5-trichloro, 3-chloro-4-bromo, 2,4-difluoro, 2,3,4-trifluoro,hydroxy and hydroxy(C₁₋₆)alkyl.

[0064] Preferably, R²¹ and R²² are both hydrogen in Formula II.

[0065] Preferably, when Ar²¹ is an unsubstituted naphthyl or a naphthylsubstituted with halogen, R²¹ and R²² are both hydrogen, and Ar²² is asubstituted phenyl group, then the substituents in Ar²² are not selectedfrom the group consisting of alkyl, haloalkyl, halogen, thiol, andnitro.

[0066] One group of novel and useful compounds of the invention arecompounds of Formula III:

[0067] or a solvate, hydrate or a pharmaceutically acceptable saltthereof, wherein

[0068] Ar³¹ is an optionally substituted aryl or an optionallysubstituted heteroaryl radical selected from the group consisting ofbiphenyl, naphthyl, tetrahydronaphthyl and isoxazolyl; and

[0069] R³³-R³⁷ are independently selected from the group consisting ofhydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol,acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl,—NHR⁴, —NR⁴R⁵, phenoxy, and phenyl(C₁₋₄)alkyloxy, wherein R⁴ is selectedfrom the group consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyland —C(O)NH-aryl, provided that at least one of R³³-R³⁷ is other thanhydrogen, with the proviso that

[0070] when Ar³¹ is an unsubstituted naphthyl or a naphthyl substitutedwith halogen, then one or more of R³³-R³⁷ is not selected from the groupconsisting of alkyl, haloalkyl, halogen, thiol, and nitro.

[0071] Preferably, Ar³¹ is optionally substituted biphenyl,tetrahydronaphthyl or isoxazolyl, more preferably optionally substitutedbiphenyl or tetrahydronaphthyl.

[0072] Optional substituents on Ar³¹ are preferably selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, hydroxy, nitro,cyano, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, and carboxy.

[0073] When Ar³¹ is tetrahydronaphthyl, it is preferably5,5,8,8-tetramethyl-substituted or3-ethyl-5,5,8,8-tetramethyl-substituted.

[0074] Preferably, R³³-R³⁷ are independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino,C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl,—C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenoxy, andbenzyloxy. More preferably, R³³-R³⁷ are independently selected from thegroup consisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,trifluoro(C₁₋₄)alkyl, hydroxy, hydroxy(C₁₋₄)alkyl, amino,amino(C₁₋₄)alkyl, C₁₋₄ alkoxy, nitro, cyano, C₁₋₄ acylamino, C₁₋₄acyloxy, carboxy, carboxy(C₁₋₄)alkyl, —C(O)O—C₁₋₄ alkyl, —C(O)NH—C₁₋₄alkyl, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, phenoxy, and benzyloxy. Mostpreferably, R³³-R³⁷ are independently selected from the group consistingof hydrogen, fluoro, chloro, bromo, trifluoromethyl, hydroxy,hydroxymethyl, hydroxyethyl, nitro, cyano, methoxy, carboxy, andbenzyloxy.

[0075] Also, one group of novel and useful compounds of the inventionare compounds of Formula IV:

[0076] or a solvate, hydrate or a pharmaceutically acceptable saltthereof, wherein

[0077] at least one of R⁴⁸-R⁴¹² is trifluoro(C₁₋₆)alkyl and thesubstitutuents that are not trifluoro(C₁₋₆)alkyl are independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl,C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl,—C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; and

[0078] R⁴³-R⁴⁷ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino,C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl, —C(O)O-C₁₋₆ alkyl,—C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenoxy, andbenzyloxy, —C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl, and—NHC(O)(C₁₋₃)alkyl, provided that at least one of R⁴³-R⁴⁷ is other thanhydrogen, with the proviso that

[0079] when one of R⁴⁸-R⁴¹² is trifluoro(C₁₋₆)alkyl and the othersubstituents are hydrogen and one of R⁴³-R⁴⁷ is halogen ortrifluoromethyl, then at least one of R⁴³-R⁴⁷ that is not halogen ortrifluoromethyl is other than hydrogen.

[0080] Preferred compounds of Formula IV include compounds wherein atleast one of R⁴⁸-R⁴¹² is trifluoromethyl.

[0081] Another group of novel and useful compounds of the invention arecompounds of Formula IV or a solvate, hydrate or a pharmaceuticallyacceptable salt thereof, wherein

[0082] at least one of R⁴⁸-R⁴¹² is nitro and the substituents that arenot nitro are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, cyano, thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆acyloxy, carboxy, carboxy(C₁₋₆)alkyl, —C(O)O-C₁₋₆ alkyl, —C(O)NH—C₁₋₆alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenoxy, benzyloxy,—C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; and

[0083] R⁴³-R⁴⁷ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, cyano, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy,carboxy, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl, provided that at least oneof R⁴³-R⁴⁷ is other than hydrogen.

[0084] Preferred compounds of Formula IV include also those, wherein atleast one of R⁴⁸-R⁴¹² is nitro and the phenyl ring is furthersubstituted by one or more C₁₋₆ alkyl groups (i.e., the other ofR⁴⁸-R⁴¹² are hydrogen or C₁₋₆ alkyl). Preferably, R⁴⁹ and R⁴¹¹ are bothnitro and R⁴¹⁰ is a C₁₋₄ alkyl group, preferably t-butyl. Optionally,the phenyl ring is further substituted by two C₁₋₃ alkyl groups.

[0085] One group of novel and useful compounds of the invention arecompounds of Formula IV or a solvate, hydrate or a pharmaceuticallyacceptable salt thereof, wherein

[0086] at least one of R⁴³-R⁴⁷ is cyano and the substitutents that arenot cyano are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy,carboxy, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; and

[0087] R⁴⁸-R⁴¹² are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino,C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl,—C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenoxy,benzyloxy, —C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl, and—NHC(O)(C₁₋₃)alkyl.

[0088] Preferred compounds of Formula IV include also compounds whereinone or more of R⁴³-R⁴⁷ are hydroxy, carboxymethyl, C₁₋₄ alkoxy, phenoxy,benzyloxy, carboxy, —C(O)O(C₁₋₃)alkyl or —O—C(O)(C₁₋₃)alkyl.

[0089] One group of useful compounds of the invention are compounds ofFormula V:

[0090] or a solvate, hydrate or a pharmaceutically acceptable saltthereof, wherein

[0091] R⁵³-R⁵⁸ are independently selected from the group consisting ofhydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol,acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl,—NHR⁴, —NR⁴R⁵, phenoxy, and benzyloxy, wherein R⁴ is selected from thegroup consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and—C(O)NH-aryl.

[0092] Preferably, R⁵³-R⁵⁸ are independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino,C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl,—C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenoxy, andbenzyloxy. More preferably, R⁵³-R⁵⁸ are independently selected from thegroup consisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,trifluoro(C₁₋₄)alkyl, hydroxy, hydroxy(C₁₋₄)alkyl, amino,amino(C₁₋₄)alkyl, C₁₋₄ alkoxy, nitro, cyano, C₁₋₄ acylamino, C₁₋₄acyloxy, carboxy, carboxy(C₁₋₄)alkyl, —C(O)O—C₁₋₄ alkyl, —C(O)NH—C₁₋₄alkyl, C₁₋₄ alkylamino, and di(C₁₋₄) alkylamino. Most preferably,R⁵³-R⁵⁸ are independently selected from the group consisting ofhydrogen, fluoro, chloro, bromo, trifluoromethyl, hydroxy,hydroxymethyl, hydroxyethyl, nitro, cyano, methoxy, and carboxy.

[0093] Also, one group of useful compounds of the invention arecompounds of Formula VI:

[0094] or a solvate, hydrate or a pharmaceutically acceptable saltthereof, wherein

[0095] Ar¹ and R³ are as defined for Formula I.

[0096] Useful compounds of the present invention include, withoutlimitation:

[0097] 1.3-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;

[0098] 2.4-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoicacid;

[0099] 3.3-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoicacid;

[0100] 4.[4-(3-bromophenyl)(1,3-thiazol-2-yl)][3-(trifluoromethyl)phenyl]amine;

[0101] 5.(3,5-dichlorophenyl)[4-(4-fluorophenyl)(1,3-thiazol-2-yl)]amine;

[0102] 6. [4-(4-bromophenyl)(1,3-thiazol-2-yl)](3-chlorophenyl)amine;

[0103] 7.[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](2,5-difluorophenyl)amine;

[0104] 8.(3,5-dichlorophenyl){4-[4-(trifluoromethyl)phenyl](1,3-thiazol-2-yl}amine;

[0105] 9. 2-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}phenol;

[0106] 10.4-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;

[0107] 11.4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;

[0108] 12.(2,4-difluorophenyl)[4-(4-chlorophenyl)-5-phenyl-1,3-thiazol-2-yl]amine;

[0109] 13.4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-1,2,3-trifluorobenzene;

[0110] 14.[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;

[0111] 15.[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](4-nitrophenyl)amine;

[0112] 16. [4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)(3,5-dichlorophenyl)amine;

[0113] 17.[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-chloro-4-bromophenyl)amine;

[0114] 18.[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-trifluoromethylphenyl)amine;

[0115] 19.[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;

[0116] 20.4-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}-1-hydroxyethylbenzene;

[0117] 21.2-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;

[0118] 22.[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;

[0119] 23.4-{[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;

[0120] 24.(4-aminophenyl)[4-(4-chlorophenyl)-5-(4-methylphenyl)-1,3-thiazol-2-yl]amine;

[0121] 25.[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;

[0122] 26.[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;

[0123] 27.[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)](3,4,5-trimethoxyphenyl)amine;

[0124] 28.3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]benzoicacid;

[0125] 29.3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]phenol;

[0126] 30.[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](4-benzyloxyphenyl)amine;

[0127] 31.[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-dimethoxyphenyl)amine;

[0128] 32.[4-(4-fluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;

[0129] 33. [4-(4-chlorophenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;

[0130] 34.[4-(3-chloro-4-methylphenyl)-5-methyl-1,3-thiazol-2-yl](3-hydroxyphenyl)amine;

[0131] 35. (4-nitrophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethylester)-1,3-thiazol-2-yl]amine;

[0132] 36. (2,4,5-trichlorophenyl)[4-(isoxazol-3-yl-5-carboxylic acidethyl ester)-1,3-thiazol-2-yl]amine; and

[0133] 37.2-cyanomethyl-4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazole.

[0134] It is also to be understood that the present invention isconsidered to include stereoisomers as well as optical isomers, e.g.mixtures of enantiomers as well as individual enantiomers anddiastereomers, which arise as a consequence of structural asymmetry inselected compounds of the present series. The methods for separating theindividual enantiomers are known to those skilled in the art.

[0135] Also, included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Examples of pharmaceutically acceptable salts includeinorganic and organic acid addition salts such as hydrochloride,hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate,fumarate, mandelate, acetic acid, dichloroacetic acid and oxalate. Acidaddition salts are formed by mixing a solution of a particularaminothiazole of the present invention with a solution of apharmaceutically acceptable non-toxic acid, such as hydrochloric acid,hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid,dichloroacetic acid, and the like. Basic salts are formed by mixing asolution of the thiazole compound of the present invention with asolution of a pharmaceutically acceptable non-toxic base, such as sodiumhydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, andthe like.

[0136] The compounds of Formula I may also be solvated, especiallyhydrated. Hydration may occur during manufacturing of the compounds orcompositions comprising the compounds, or the hydration may occur overtime due to the hygroscopic nature of the compounds.

[0137] The term “aryl” as employed herein by itself or as part ofanother group refers to monocyclic or bicyclic aromatic groupscontaining from 6 to 12 carbons in the ring portion, such as phenyl,biphenyl, naphthyl or tetrahydronaphthyl. Preferably, the aryl groupcontains 6-10 carbons in the ring portion.

[0138] The term “heteroaryl” as employed herein refers to groups having5 to 14 ring atoms; 6, 10 or 14 π electrons shared in a cyclic array;and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl,pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl,phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl,pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, thiazolyl,isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinylgroups).

[0139] The term “alkyl” as employed herein by itself or as part ofanother group refers to both straight and branched chain radicals of upto 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. Preferably, thealkyl chain is 1 to 6 carbon atoms in length, more preferably 1 to 4carbon atoms in length.

[0140] The term “cycloalkyl” as employed herein by itself or as part ofanother group refers to cycloalkyl groups containing 3 to 9 carbonatoms, preferably 3 to 7 carbon atoms. Typical examples are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl andcyclononyl.

[0141] The term “aroyl” as employed herein refers to the radical R—CO—,wherein R is any of the above aryl and heteroaryl groups.

[0142] Useful halogen groups include fluorine, chlorine, bromine andiodine.

[0143] Useful haloalkyl groups include C₁₋₁₂ alkyl groups substituted byone or more fluorine, chlorine, bromine or iodine atoms, e.g.,fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,1,1-difluoroethyl and trichloromethyl groups.

[0144] Useful hydroxyalkyl groups include include C₁₋₁₂ alkyl groupssubstituted by hydroxy, e.g., hydroxymethyl, hydroxyethyl, hydroxypropyland hydroxybutyl groups.

[0145] Useful alkoxy groups include oxygen substituted by one of theC₁₋₁₂ alkyl groups mentioned above.

[0146] Useful acylamino groups are any acyl group, particularly C₂₋₆alkanoyl or C₆₋₁₀ aryl(C₂₋₆)alkanoyl attached to an amino nitrogen,e.g., acetamido, propionamido, butanoylamido, pentanoylamido,hexanoylamido, and benzoylamido.

[0147] Useful acyloxy groups are any C₁₋₆ acyl (alkanoyl) attached to anoxy (—O—) group, e.g., acetoxy, propionyloxy, bytanoyloxy, pentanoyloxy,hexanoyloxy and the like.

[0148] Useful alkylamino and dialkylamino groups are —NHR⁶ and —NR⁶R⁷,wherein R⁶ and R⁷C₁₋₆ alkyl groups.

[0149] Optional substituents on Ar¹, Ar²¹, Ar³¹, Ar², Ar²², R¹ and R³include any one of halogen, haloalkyl, cycloalkyl, alkyl,cycloalkylalkyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, nitro, amino,cyano, acylamino, hydroxy, thiol, acyloxy, alkoxy, carboxy,—C(O)O-alkyl, —O—C(O)-alkyl, —C(O)NH-alkyl, aryloxy, arylalkyloxy,—NHR⁴, —NR⁴R⁵ wherein R⁴ and R⁵ are selected from the group consistingof C₁₋₆ alkyl, —C(O)(C₁₋₆)alkyl, aroyl, —C(O)NH(C₁₋₃)alkyl and—C(O)NH-aryl. More preferably the optional substituents include halogen,halo(C₁₋₆)alkyl, cycloalkyl, C₁₋₆ alkyl, cycloalkyl(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro,amino, cyano, C₁₋₆ acylamino, hydroxy, thiol, C₁₋₆ acyloxy, C₁₋₆ alkoxy,carboxy, di(C₁₋₆)alkylamino, —C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl,—C(O)NH(C₁₋₃)alkyl, aryloxy, aryl(C₁₋₆)oxy, —NHR⁴, wherein R⁴ isselected from the group consisting of C₁₋₆ alkyl, —C(O)(C₁₋₆)alkyl,aroyl, —C(O)NH(C₁₋₃)alkyl and —C(O)NH-aryl.

[0150] The compounds of the invention may be prepared using methodsknown for the skilled person in the art. For example, compounds ofFormula I, wherein Y is —N— or —C(R³)— can be prepared by allowing abromoketone of the Formula VII:

[0151] wherein Ar¹ and R¹ are as defined above, to react with a mono- or-di-substituted thiourea of Formula VIII:

[0152] wherein Ar², R² and R³ are as defined above, in an appropriatesolvent, such as acetone or DMF, for a sufficient time period.

[0153] Compounds of Formula I, wherein Y is —CH(R³)— can be prepared byallowing a bromoketone of the Formula VII to react with a thiourea ofFormula IX:

[0154] wherein R² and R³ are as defined above, in an appropriate solventfor a sufficient time period.

[0155] The starting materials, e.g., the compounds of Formula VII, VIIIand IX are either known or may be produced in known manner or analogousto the methods described herein.

[0156] PAI-1 Assay

[0157] The inhibitory activity of PAI-1 against uPA was measured by adirect chromogenic assay using the substrate N-CBZ-VAL-GLY-ARGp-nitroanilide. The tested compound was added to PAI-1 which had beendiluted in activity assay buffer (0.05M Hepes, pH 7.5, 0.15M NaCl,containing 0.05% N-octyl-D-glucopyranoside and 250 μg/ml bovine serumalbumin). After a 10 minute incubation at 37° C., uPA was added (0.04units/assay), followed immediately by the addition of substrate. Afterreequilibration at 37° C., residual uPA activity was quantified bymeasuring the change in absorbance at 405 nm over 12 minutes. Theconcentration of active PAI-1 in the assays was the amount required toinhibit 80-85% of uPA as compared to samples containing uPA alone.

[0158] Compositions within the scope of the invention include allcompositions wherein the compounds of the present invention arecontained in an amount that is effective to achieve its intendedpurpose. While individual needs vary, determination of optimal ranges ofeffective amounts of each component is within the skill of the art.Typically, the compounds may be administered to mammals, e.g., humans,orally at a dose of 1 to 1000 mg/kg, or an equivalent amount of thepharmaceutically acceptable salt thereof, per day of the body weight ofthe mammal being treated for thrombosis, angina pectoris, cerebralinfarction, myocardial infarction, pulmonary infarction, intra-atrialthrombus in atrial fibrillation, deep venous thrombus, disseminatedintravascular coagulation syndrome, diabetic complications, restenosisafter percutaneous transluminal coronary angioplasty and stroke. Forintramuscular injection, the dose is generally about one-half of theoral dose.

[0159] The unit oral dose may comprise from about 1 to about 1000 mg,preferably about 1 to about 100 mg of the compound. The unit dose may beadministered one or more times daily as one or more tablets eachcontaining from about 0.1 to about 50, conveniently about 0.25 to about100 mg of the compound or its solvates.

[0160] In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, containing from about 0.01 to 99 percent,preferably from about 0.25 to about 75 percent of active compound(s),together with the excipient.

[0161] The pharmaceutical compositions of the invention may beadministered to any animal that may experience the beneficial effects ofthe compounds of the invention. Foremost among such animals are mammals,e.g. humans, although the invention is not intended to be so limited.

[0162] The pharmaceutical compositions of the invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, or buccal routes.Alternatively, or concurrently, administration may be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the desired effect.

[0163] The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

[0164] Suitable excipients are, in particular, fillers, such assaccharides, for example, lactose or sucrose, mannitol or sorbitol,cellulose preparations and/or calcium phosphates, for example tricalciumphosphate or calcium hydrogen phosphate, as well as binders such asstarch paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents may be addedsuch as the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings which, if desired, are resistant to gastric juices.For this purpose, concentrated saccharine solutions may be used, whichmay optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

[0165] Other pharmaceutical preparations which can be used orallyinclude push-fit capsules made of gelatin, as well as soft, sealedcapsules made of gelatin and a plasticizer such as glycerol or sorbitol.The push-fit capsules can contain the active compounds in the form ofgranules which may be mixed with fillers such as lactose, binders suchas starches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

[0166] Possible pharmaceutical preparations, which can be used rectally,include, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0167] Suitable formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form, forexample, water soluble salts and alkaline solutions. In addition,suspensions of the active compounds as appropriate oily injectionsuspensions may be administered. Suitable lipophilic solvents orvehicles include fatty oils, for example, sesame oil, or synthetic fattyacid esters, for example, ethyl oleate or triglycerides or polyethyleneglycol-400 (the compounds are soluble in PEG-400). Aqueous injectionsuspensions may contain substances which increase the viscosity of thesuspension, and include, for example, sodium carboxymethyl cellulose,sorbitol, and/or dextran. Optionally, the suspension may also containstabilizers.

[0168] The following examples are illustrative, but not limiting, of themethod and compositions of the present invention. Other suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art within the spirit and scope of theinvention.

EXAMPLE 1

[0169] The following compounds were prepared according to the methoddescribed above by suspending a solution of a suitably substitutedthiourea or thioamide (2 mmol) and a suitably substituted α-haloketone(2 mmol) in acetone and then heating the suspension to reflux at 55° C.for 12 hours. The product precipitated as a white solid. The product wasfiltrated and washed with cold acetone to afford the pure product as awhite solid.

[0170] In cases where the product did not precipitate, the solvent wasremoved under reduced pressure to give the pure 2-substituted thiazoleas a white solid.

[0171]3-{[4-(5,5,8,8-tetrametyl-2-5,6,7,8-tetrahydronaphtyl)-1,3-thiazol-2-yl]amino}phenol;¹H NMR (δ, DMSO): 1.26 (s, 6H), 1.30 (s, 6H), 1.66 (s, 4H), 6.43 (d,1H), 7.04-7.82 (m, 7H); MS: M+1=379 (calculated 378).

[0172]4-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphtyl)-1,3-thiazol-2-yl]amino}benzoicacid; ¹H NMR (δ, DMSO): 1.08-1.12 (t, 3H), 1.25 (s, 6H), 1.26 (s, 6H),1.64 (s, 4H), 2.73-2.79 (m, 2H), 6.94 (s, 1H), 7.20-7.87 (m, 6H); MS:M+1=435 (calculated 434).

[0173]3-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronapthyl)-1,3-thiazol-2-yl]amino}benzoicacid; ¹H NMR (δ, DMSO): 1.08-1.12 (t, 3H), 1.26 (s, 6H), 1.27 (s, 6H),1.65 (s, 4H), 2.76-2.81 (m, 2H), 6.89 (s, 1H), 7.21-8.34 (m, 6H); MS:M+1=435 (calculated 434).

[0174][4-(3-bromophenyl)-1,3-thiazol-2-yl][3-(trifluoromethyl)-phenylamine; ¹HNMR (δ, DMSO):7.30-8.46 (m, 9H), 10.74 (s, 1H); MS: M+1=399 (calculated398).

[0175] (3,5-dichlorophenyl)[4-(4-fluorophenyl)(1,3-thiazol-2yl)]amine;¹H NMR (δ, DMSO): 7.12-7.94 (m, 9H), 10.80 (s, 1H); MS: M+1=339, M+3=341(calculated 338).

[0176] [4-(4-bromophenol)(1,3-thiazol-2-yl)](3-chlorophenyl)amine: ¹HNMR (δ, DMSO): 6.98-7.92 (m, 9H); MS: M+1=365, M+3=367 (calculated 364).

[0177][4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](2,5-difluorophenyl)amine: ¹HNMR (δ, DMSO): 6.80-6.84 (t, 1H), 7.28-7.34 (m, 1H), 7.67-8.53 (m, 5H),10.44 (s, 1H); MS: M+1=359, M+3=359 (calculated 356).

[0178](3,5-dichlorophenyl){4-[4-(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}amine;¹H NMR (δ, DMSO): 7.12-7.15 (m, 1H), 7.68-7.87 (m, 5H), 8.07-8.09 (d,2H), 10.80 (s, 1H); MS: M+1=389, M+3=391 (calculated 388).

[0179] 4-{[4-(4-bromophenyl)-1,3-thiazol-2-yl amino}benzenecarbonitrile;¹H NMR (δ, DMSO): 7.58 (s, 1H), 7.62-7.65 (m, 2H), 7.78-7.82 (m, 2H),7.89-7.96 (m, 4H), 11.01 (s, 1H); MS: M+1=356, M+3=358 (calculated 355).

[0180]4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile; ¹HNMR (δ, CDCl₃): 6.92 (s, 1H), 7.38-7.85 (m, 13H), 11.61 (s, 1H); MS:M+1=354 (calculated 353).

EXAMPLE 2

[0181] Optionally substituted thiourea or thioamide (0.075 mmol) in DMF(0.25 mL) and an optionally substituted α-haloketone in DMF (0.25 mL)were added to a 2 mL Robbins 96 well plate. The reaction mixture wasshaken for 2 days at 75° C., and subsequently the solvent was evaporatedto dryness using a Savant speedvac to give the pure 2-substitutedthiazole.

EXAMPLE 3

[0182] Activity of Compounds 1 to 37 as PAI-1 Inhibitors

[0183] Compounds No. 1 to 37 were tested in the PAI-1 assay as describedabove. The compounds exhibited PAI-1 inhibitory activity in vitro withIC₅₀ value of between 1.1 and 18.5 μM. Compound 3 had an IC₅₀ value of1.1 μM, compound 11 had an IC₅₀ value of 1.6 μM, and compound 2 had anIC₅₀ value of 1.8 μM.

[0184] Those skilled in the art will recognize that while specificembodiments have been illustrated and described, various modificationsand changes may be made without departing from the spirit and scope ofthe invention.

[0185] Other embodiments of the invention will be apparent to thoseskilled in the art from consideration of the specification and practiceof the invention disclosed herein. It is intended that the specificationand examples be considered as exemplary only, with a true scope andspirit of the invention being indicated by the following claims. Allpublications, patent applications and patents cited herein are fullyincorporated by reference.

What is claimed is:
 1. A method of inhibiting plasminogen activatorinhibitor-1, comprising administering to a mammal in need thereof aneffective amount of a compound of Formula I:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein Y is —N—, —C(R³)— or —CH(R³)—, wherein R³ is selected from thegroup consisting of hydrogen, cyano, C(CN)₃, N(CN)₂, trifluoromethyl,halogen, alkyl, cycloalkyl, aryl and heteroaryl radical, all of whichcan be optionally substituted; Ar¹ and Ar², which can be the same ordifferent, are an optionally substituted aryl or heteroaryl radical; mis 0 or 1, provided that when Y is —N— or —C(R³)—, then m is 1 and whenY is —CH(R³)—, then m is 0; R¹ is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, and aryl or heteroaryl radical, all ofwhich can be optionally substituted; and R² is hydrogen, or anoptionally substituted aryl or an optionally substituted heteroarylradical; with the provisos that when Y is N, R¹ and R² are hydrogen andAr² is an optionally substituted phenyl, then Ar¹ is other than a phenylgroup substituted with carboxyalkyl or an alkyl ester ofcarboxyalkyloxy; when Y is N, R¹ is hydrogen, and Ar² and R² are both aphenyl group, then Ar¹ is other than a phenyl group substituted withcarboxyalkyl; or when Y is N, R¹ and R² are hydrogen and Ar² isnaphthyl, then Ar¹ is other than a phenyl group substituted withcarboxyalkyl.
 2. The method according to claim 1 , wherein Ar¹ and Ar²are independently selected from the group consisting of phenyl,biphenyl, naphthyl, tetrahydronaphthyl, thienyl, benzothienyl, furyl,benzofuryl, thiazolyl, imidazolyl, isoxazolyl, pyrrolyl and pyrazolyl,any of which can be optionally substituted.
 3. The method according toclaim 1 , wherein R¹ and R² both are hydrogen.
 4. The method accordingto claim 1 , wherein the compound administered is a compound of FormulaII:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein Ar²¹ is an optionally substituted aryl or an optionallysubstituted heteroaryl radical; Ar²² is a substituted aryl or anoptionally substituted heteroaryl radical; R²¹ is selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroarylradical, all of which can be optionally substituted; R²² is hydrogen, oran optionally substituted aryl or an optionally substituted heteroarylradical, with the provisos that when R²¹ and R²² are hydrogen and Ar²²is substituted phenyl, then Ar²¹ is other than a phenyl groupsubstituted with carboxyalkyl; when R²¹ is hydrogen, and Ar²² and R²²are both a phenyl group, then Ar²¹ is other than a phenyl groupsubstituted with carboxyalkyl; or when R²¹ and R²² are hydrogen and Ar²²is naphthyl, then Ar²¹ is other than a phenyl group substituted withcarboxyalkyl.
 5. The method according to claim 4 , wherein the aryl orheteroaryl radical is selected from the group consisting of phenyl,biphenyl, naphthyl, tetrahydronapthyl and isoxazolyl.
 6. The methodaccording to claim 4 , wherein the compound administered is a compoundof Formula III:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein Ar³¹ is an optionally substituted aryl or an optionallysubstituted heteroaryl radical selected from the group consisting ofbiphenyl, naphthyl, tetrahydronaphthyl and isoxazolyl; and R³³-R³⁷ areindependently selected from the group consisting of hydrogen, alkyl,halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy,alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino, acyloxy,carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR⁴, —NR⁴R⁵,phenoxy, and phenyl(C₁₋₄)alkyloxy, wherein R⁴ is selected from the groupconsisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and—C(O)NH-aryl, provided that at least one of R³³-R³⁷ is other thanhydrogen.
 7. The method according to claim 4 , wherein the compoundadministered is a compound of Formula IV:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein at least one of R⁴⁸-R⁴¹² is trifluoro(C₁₋₆)alkyl and thesubstituents that are not trifluoro(C₁₋₆)alkyl are independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl,C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl,—C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; and R⁴³-R⁴⁷ areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano,thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy,carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, phenoxy, and benzyloxy,—C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl, providedthat at least one of R⁴³-R⁴⁷ is other than hydrogen.
 8. The methodaccording to claim 4 , wherein the compound administered is a compoundof Formula IV:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein at least one of R⁴⁸-R⁴¹² is nitro and the substituents that arenot nitro are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, cyano, thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆acyloxy, carboxy, carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenoxy, benzyloxy,—C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; andR⁴³-R⁴⁷ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, cyano, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy,carboxy, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino, di-C₁₋₆alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl,and —NHC(O)(C₁₋₃)alkyl, provided that at least one of R⁴³-R⁴⁷ is otherthan hydrogen.
 9. The method according to claim 4 , wherein the compoundadministered is a compound of Formula IV:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein at least one of R⁴³-R⁴⁷ is cyano and the substitutents that arenot cyano are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy,carboxy, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, benzyloxy, C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; and R⁴⁸-R⁴¹² areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano,thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy,carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl.
 10. The method according toclaim 1 , wherein the compound administered is a compound of Formula V:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein R⁵³-R⁵⁸ are independently selected from the group consisting ofhydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol,acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl,—NHR⁴, —NR⁴R⁵, phenoxy, and benzyloxy, wherein R⁴ is selected from thegroup consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and—C(O)NH-aryl.
 11. The method according to claim 1 , wherein the compoundadministered is a compound of Formula VI:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein Ar¹ and R³ are as defined in claim 1 .
 12. The method accordingto claim 1 , wherein the compound administered is selected from thegroup consisting of3-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;4-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoicacid;3-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoicacid;[4-(3-bromophenyl)(1,3-thiazol-2-yl)][3-(trifluoromethyl)phenyl]amine;(3,5-dichlorophenyl)[4-(4-fluorophenyl)(1,3-thiazol-2-yl)]amine;[4-(4-bromophenyl)(1,3-thiazol-2-yl)](3-chlorophenyl)amine;[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](2,5-difluorophenyl)amine;(3,5-dichlorophenyl){4-[4-(trifluoromethyl)phenyl](1,3-thiazol-2-yl}amine;2-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}phenol;4-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;(2,4-difluorophenyl)[4-(4-chlorophenyl)-5-phenyl-1,3-thiazol-2-yl]amine;4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-1,2,3-trifluorobenzene;[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](4-nitrophenyl)amine;[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-chloro-4-bromophenyl)amine;[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-trifluoromethylphenyl)amine;[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;4-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}-1-hydroxyethylbenzene;2-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;4-{[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;(4-aminophenyl)[4-(4-chlorophenyl)-5-(4-methylphenyl)-1,3-thiazol-2-yl]amine;[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)](3,4,5-trimethoxyphenyl)amine;3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]benzoicacid;3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]phenol;[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](4-benzyloxyphenyl)amine;[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-dimethoxyphenyl)amine;[4-(4-fluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;[4-(4-chlorophenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;[4-(3-chloro-4-methylphenyl)-5-methyl-1,3-thiazol-2-yl](3-hydroxyphenyl)amine;(4-nitrophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethylester)-1,3-thiazol-2-yl]amine;(2,4,5-trichlorophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethylester)-1,3-thiazol-2-yl]amine; and2-cyanomethyl-4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazole.or a solvate, hydrate or a pharmaceutically acceptable salt thereof. 13.The method according to claim 1 , wherein one or more of thrombosis,myocardial infarction, pulmonary infarction, intra-atrial thrombus inatrial fibrillation, deep venous thrombus, disseminated intravascularcoagulation syndrome, diabetic complications, restenosis or stroke aretreated.
 14. A compound having the Formula II:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein Ar²¹ is an optionally substituted aryl or an optionallysubstituted heteroaryl radical; Ar²² is a substituted aryl or anoptionally substituted heteroaryl radical; R²¹ is selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, and aryl or heteroarylradical, all of which can be optionally substituted; R²² is hydrogen, oran optionally substituted aryl or an optionally substituted heteroarylradical, with the provisos that when R²¹ and R²² are hydrogen and Ar²²is substituted phenyl, then Ar²¹ is other than a phenyl groupsubstituted with carboxyalkyl; when R²¹ is hydrogen, and Ar²² and R²²are both a phenyl group, then Ar²¹ is other than a phenyl groupsubstituted with carboxyalkyl; when R²¹ and R²² are hydrogen and Ar²² isnaphthyl, then Ar²¹ is other than a phenyl group substituted withcarboxyalkyl; when Ar²¹ an unsubstituted naphthyl or a naphthylsubstituted with halogen, R²¹ and R²² are both hydrogen and Ar²² is asubstituted phenyl group, then the substituents in Ar²² are not selectedfrom the group consisting of alkyl, haloalkyl, halogen, thiol, andnitro; or when Ar²¹ is a phenyl group substituted only withtrifluoro(C₁₋₆)alkyl, R²¹ and R²² are both hydrogen, and Ar²² is aphenyl group substituted with halogen or trifluoromethyl, then Ar²² hasanother substituent other than hydrogen.
 15. The compound according toclaim 14 , wherein the aryl or heteroaryl radical is selected from thegroup consisting of phenyl, biphenyl, naphthyl, tetrahydronapthyl andisoxazolyl.
 16. The compound according to claim 15 , wherein Ar²² is aphenyl group substituted with one or more of alkyl, halogen, haloalkyl,hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, alkoxyalkyl, nitro,cyano, thiol, alkylthiol, acylamino, acyloxy, carboxy, carboxyalkyl,—C(O)O-alkyl, —C(O)NH-alkyl, —NHR⁴, —NR⁴R⁵, phenoxy, and benzyloxy,wherein R⁴ is selected from the group consisting of alkyl, —C(O)O-alkyl,aroyl, —C(O)NH-alkyl and —C(O)NH-aryl.
 17. The compound according toclaim 16 , wherein Ar²² is a phenyl group substituted with one or moreof C₁₋₆ alkyl, fluoro, chloro, bromo, trifluoro(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, nitro, cyano,carboxy, —C(O)O—(C₁₋₆)alkyl and benzyloxy.
 18. The compound according toclaim 17 , wherein Ar²² is a phenyl group substituted with carboxy,cyano, nitro, trifluoromethyl, 3,5-dichloro, 3,4-dichloro, 2,4-dichloro,2,4,5-trichloro, 3-chloro-4-bromo, 2,4-difluoro, 2,3,4-trifluoro,hydroxy and hydroxy(C₁₋₆)alkyl.
 19. The compound according to claim 18 ,wherein Ar²¹ is a phenyl group substituted with 3,4-difluoro,2,4-difluoro, bromo, trifluoromethyl, 3,4-dichloro, and 2,4-dichloro.20. The compound according to claim 14 , wherein R²¹ and R²² are bothhydrogen.
 21. A compound according to claim 14 having the Formula III:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein Ar³¹ is an optionally substituted aryl or an optionallysubstituted heteroaryl radical selected from the group consisting ofbiphenyl, naphthyl, tetrahydronaphthyl and isoxazolyl; and R³³-R³⁷ areindependently selected from the group consisting of hydrogen, alkyl,halogen, haloalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy,alkoxyalkyl, nitro, cyano, thiol, alkylthiol, acylamino, acyloxy,carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl, —NHR⁴, —NR⁴R⁵,phenoxy, and phenyl(C₁₋₄)alkyloxy, wherein R⁴ is selected from the groupconsisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and—C(O)NH-aryl, provided that at least one of R³³-R³⁷ is other thanhydrogen, with the proviso that when Ar³¹ an unsubstituted naphthyl or anaphthyl substituted with halogen, then one or more of R³³-R³⁷ is notselected from the group consisting of alkyl, haloalkyl, halogen, thiol,and nitro.
 22. The compound according to claim 21 , wherein Ar³¹ is anoptionally substituted biphenyl, tetrahydronaphthyl or isoxazolyl. 23.The compound according to claim 22 , wherein Ar³¹ is an optionallysubstituted biphenyl or tetrahydronaphthyl.
 24. The compound accordingto claim 21 , wherein the optional substituent on Ar³¹ is selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, halogen, hydroxy, nitro,cyano, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, and carboxy.
 25. Thecompound according to claim 21 , wherein R³³-R³⁷ are independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl,C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl,—C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, and benzyloxy.
 26. The compound accordingto claim 25 , wherein R³³-R³⁷ are independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, halogen, halo(C₁₋₄)alkyl,trifluoro(C₁₋₄)alkyl, hydroxy, hydroxy(C₁₋₄)alkyl, amino,amino(C₁₋₄)alkyl, C₁₋₄ alkoxy, nitro, cyano, C₁₋₄ acylamino, C₁₋₄acyloxy, carboxy, carboxy(C₁₋₄)alkyl, —C(O)O—C₁₋₄ alkyl, —C(O)NH—C₁₋₄alkyl, C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, phenoxy, and benzyloxy. 27.The compound according to claim 26 , wherein R³³-R³⁷ are independentlyselected from the group consisting of hydrogen, fluoro, chloro, bromo,trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, nitro, cyano,methoxy, carboxy, and benzyloxy.
 28. A compound according to claim 14having the Formula IV:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein at least one of R⁴⁸-R⁴¹² is trifluoro(C₁₋₆)alkyl and thesubstituents that are not trifluoro(C₁₋₆)alkyl are independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl,C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano, thiol, C₁₋₆alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy, carboxy(C₁₋₆)alkyl,—C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; and R⁴³-R⁴⁷ areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano,thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy,carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, phenoxy, and benzyloxy,—C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl, providedthat at least one of R⁴³-R⁴⁷ is other than hydrogen, with the provisothat when one of R⁴⁸-R⁴¹² is trifluoro(C₁₋₆)alkyl and the othersubstituents are hydrogen and one of R⁴³-R⁴⁷ is halogen ortrifluoromethyl, then at least one of R⁴³-R⁴⁷ that is not halogen ortrifluoromethyl, is other than hydrogen.
 29. A compound according toclaim 14 having the Formula IV:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein at least one of R⁴⁸-R⁴¹² is nitro and the substituents that arenot nitro are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, cyano, thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆acyloxy, carboxy, carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, phenoxy, benzyloxy,—C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; andR⁴³-R⁴⁷ are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, cyano, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy,carboxy, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino, di-C₁₋₆alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl, —O—C(O)(C₁₋₃)alkyl,and —NHC(O)(C₁₋₃)alkyl, provided that at least one of R⁴³-R⁴⁷ is otherthan hydrogen.
 30. A compound according to claim 14 having the FormulaIV:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein at least one of R⁴³-R⁴⁷ is cyano and the substitutents that arenot cyano are independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy,carboxy, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl; and R⁴⁸-R⁴¹² areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, halo(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, nitro, cyano,thiol, C₁₋₆ alkylthiol, C₁₋₆ acylamino, C₁₋₆ acyloxy, carboxy,carboxy(C₁₋₆)alkyl, —C(O)O—C₁₋₆ alkyl, —C(O)NH—C₁₋₆ alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, phenoxy, benzyloxy, —C(O)O(C₁₋₃)alkyl,—O—C(O)(C₁₋₃)alkyl, and —NHC(O)(C₁₋₃)alkyl.
 31. A compound having theFormula V:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein R⁵³-R⁵⁸ are independently selected from the group consisting ofhydrogen, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, amino,aminoalkyl, alkoxy, alkoxyalkyl, nitro, cyano, thiol, alkylthiol,acylamino, acyloxy, carboxy, carboxyalkyl, —C(O)O-alkyl, —C(O)NH-alkyl,—NHR⁴, —NR⁴R⁵, phenoxy, and benzyloxy, wherein R⁴ is selected from thegroup consisting of alkyl, —C(O)O-alkyl, aroyl, —C(O)NH-alkyl and—C(O)NH-aryl.
 32. A compound having the Formula VI:

or a solvate, hydrate or a pharmaceutically acceptable salt thereof,wherein R³ is selected from the group consisting of hydrogen, cyano,C(CN)₃, N(CN)₂, trifluoromethyl, halogen, alkyl, cycloalkyl, aryl andheteroaryl radical, all of which can be optionally substituted; and Ar¹is an optionally substituted aryl or an optionally substitutedheteroaryl radical.
 33. The compound according to claim 32 , wherein Ar¹selected from the group consisting of phenyl, biphenyl, naphthyl,tetrahydronaphthyl, thienyl, benzothienyl, furyl, benzofuryl, thiazolyl,imidazolyl, isoxazolyl, pyrrolyl and pyrazolyl, any of which can beoptionally substituted.
 34. The compound according to claim 33 , whereinAr¹ is selected from the group consisting of phenyl, naphthyl,tetrahydronaphthyl, biphenyl and isoxazolyl.
 35. A compound selectedfrom the group consisting of3-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;4-{[4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoicacid;3-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}benzoicacid;[4-(3-bromophenyl)(1,3-thiazol-2-yl)][3-(trifluoromethyl)phenyl]amine;(3,5-dichlorophenyl)[4-(4-fluorophenyl)(1,3-thiazol-2-yl)]amine;[4-(4-bromophenyl)(1,3-thiazol-2-yl)](3-chlorophenyl)amine;[4-(3,4-dichlorophenyl)(1,3-thiazol-2-yl)](2,5-difluorophenyl)amine;(3,5-dichlorophenyl){4-[4-(trifluoromethyl)phenyl](1,3-thiazol-2-yl}amine;2-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}phenol;4-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-benzenecarbonitrile;(2,4-difluorophenyl)[4-(4-chlorophenyl)-5-phenyl-1,3-thiazol-2-yl]amine;4-{[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino}-1,2,3-trifluorobenzene;[4-(3,4-difluorophenyl)(1,3-thiazol-2[-yl) (3,4-dichlorophenyl)-amine;[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](4-nitrophenyl)amine;[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-chloro-4-bromophenyl)amine;[4-(3,4-difluorophenyl)(1,3-thiazol-2-yl)](3-trifluoromethylphenyl)amine;[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;4-{4-(3-ethyl-5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}-1-hydroxyethylbenzene;2-{[4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazol-2-yl]amino}phenol;[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;4-{[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}benzenecarbonitrile;(4-aminophenyl)[4-(4-chlorophenyl)-5-(4-methylphenyl)-1,3-thiazol-2-yl]amine;[4-(2,4-difluorophenyl)(1,3-thiazol-2-yl)](3,5-dichlorophenyl)amine;[4-(4-trifluoromethylphenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)](3,4,5-trimethoxyphenyl)amine;3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]benzoicacid;3-[4-(4-tert-butyl-2,6-dimethyl-3,5-dinitrophenyl)(1,3-thiazol-2-yl)amino]phenol;[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-benzyloxyphenyl)amine;[4-(4-nitrophenyl)(1,3-thiazol-2-yl)](2,4-dimethoxyphenyl)amine;[4-(4-fluorophenyl)(1,3-thiazol-2-yl)](3,4-dichlorophenyl)amine;[4-(4-chlorophenyl)(1,3-thiazol-2-yl)](3-hydroxyphenyl)amine;[4-(3-chloro-4-methylphenyl)-5-methyl-1,3-thiazol-2-yl](3-hydroxyphenyl)amine;(4-nitrophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethylester)-1,3-thiazol-2-yl]amine;(2,4,5-trichlorophenyl)[4-(isoxazol-3-yl-5-carboxylic acid ethylester)-1,3-thiazol-2-yl]amine; and2-cyanomethyl-4-(5,5,8,8-tetramethyl-2-5,6,7,8-tetrahydronaphthyl)-1,3-thiazole;or a solvate, hydrate or a pharmaceutically acceptable salt thereof.